This invention relates to a pharmaceutical composition comprising a compound of the camptothecin analog class and a platinum coordination compound and a pharmaceutically acceptable carrier or diluent. This invention also relates to a method of inhibiting the growth of tumor cells in a human afflicted therewith which comprises administering to such human an effective tumor cell growth inhibiting amount of such pharmaceutical composition. This invention also relates to a method of inhibiting the growth of tumor cells in a human afflicated therewith which comprises administering to such human an effective tumor cell growth inhibiting amount of the combination of a compound of the camptothecin analog class and a platinum coordination compound.
Cisplatin, or cis-dichlorodiammineplatinum II, has been used successfully for many years as a chemotherapeutic agent in the treatment of various human solid malignant tumors. More recently, other diamino-platinum complexes have also shown efficacy as chemotherapeutic agents in the treatment of various human solid malignant tumors. Such diamino-platinum complexes include, but are not limited to, spiroplatinum and carboplatinum.
Although cisplatin and other diamino-platinum complexes have been widely used as chemotherapeutic agents in humans, they are not therapeutically effective in all patients or agaisnt all types of solid tumors. Moreover, such compounds have to be delivered at high dosage levels which can lead to toxicity problems such as kidney damage.
Topotecan and every compound of the camptothecin analog class are each a specific inhibitor of DNA topoisomerase I. Topoisomerases are enzymes that are capable of altering DNA topology in eukaryotic cells. They are critical for important cellular functions and cell proliferation. There are two classes of topoisomerases in eukaryotic cells, type I and type II. Topoisomerase I is a monomeric enzyme of approximately 100,000 molecular weight. The enzyme binds to DNA and introduces a transient single-strand break, unwinds the double helix (or allows it to unwind), and subsequently reseals the break before dissociating from the DNA strand. Topotecan has recently shown clinical efficacy as the sole chemotherapeutic agent in the treatment of humans afflicated with ovarian cancer, esophageal cancer or non-small cell lung carcinoma.
There is a need for increasing the efficacy of the tumor cell growth inhibiting activity of cisplatin and other diamino-platinum complexes and/or providing a means for the use of lower dosages of cisplatin and other diamino-platinum complexes to reduce the potential of adverse toxic side effects to the patient.
The pharmaceutical composition and methods of this invention fill such a need. It has now been found that a compound of the camptothecin analog class, such as topotecan, demonstrates a therapeutic synergism when administered with a platinum coordination compound, such as cisplatin, thereby potentially increasing the tumor cell growth inhibiting activity of such platinum coordination compound. It has also now been found that such synergism likely results in a need for lower doses of such platinum coordination compound when administered with a compound of the camptothecin analog class as compared to the doses required when such platinum coordination compound is administered without a compound of the camptothecin analog class.